title: Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.
abstract: OBJECTIVE
  The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).
  
  
  METHODS
  In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).
  
  
  RESULTS
  A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.
  
  
  CONCLUSIONS
  Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
authors.affiliation: Lecia V. Sequist, Massachusetts General Hospital and Harvard Medical School, Boston, MA; James Chih-Hsin Yang, National Taiwan University Hospital; Chun-Ming Tsai, Taipei Veterans General Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Nobuyuki Yamamoto, Shizuoka Cancer Center, Shizuoka; Terufumi Kato, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; Kenneth O'Byrne, St James' Hospital, Dublin, Ireland; Vera Hirsh, McGill University, Montreal, Quebec, Canada; Tony Mok, Prince of Wales Hospital, Hong Kong, China; Sarayut Lucien Geater, Songklanagarind Hospital, Songkla, Thailand; Sergey Orlov, Pavlov State Medical University, St Petersburg; Vera Gorbunova, GU Russian Oncological Research Centre, Moscow, Russia; Michael Boyer, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Jaafar Bennouna, Institut de Cancérologie de l'Ouest-site René Gauducheau, Nantes, France; Ki Hyeong Lee, Chungbuk National University Hospital, Cheongju, South Korea; Riyaz Shah, Maidstone and Tunbridge Wells National Health Service Trust, Maidstone Hospital, Maidstone; Dan Massey, Victoria Zazulina, and Mehdi Shahidi, Boehringer Ingelheim, Bracknell, United Kingdom; and Martin Schuler, West German Cancer Center, University of Duisburg-Essen, Essen, Germany.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.forename: Sarayut Lucien
authors.initials: SL
authors.lastname: Geater
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.forename: Michael
authors.initials: M
authors.lastname: Boyer
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kato
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.forename: Ki Hyeong
authors.initials: KH
authors.lastname: Lee
authors.forename: Riyaz
authors.initials: R
authors.lastname: Shah
authors.forename: Dan
authors.initials: D
authors.lastname: Massey
authors.forename: Victoria
authors.initials: V
authors.lastname: Zazulina
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shahidi
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D000068437:Pemetrexed; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D005971:Glutamates; D011799:Quinazolines; D000068437:Pemetrexed; D000077716:Afatinib; D006147:Guanine; D066246:ErbB Receptors; D002945:Cisplatin